Project Summary The innate immune system is strongly implicated in the pathogenesis of Alzheimer's disease (AD). In contrast, the role of adaptive immunity and peripheral lymphocytes in AD remains largely unexplored. Yet, new studies have begun to implicate these cells in the development and progression of AD in mouse models. For example, we recently found that genetic deletion of T, B, and NK cells in transgenic AD mice leads to dramatic increase in A? pathology. Conversely, replacement of these populations via bone marrow transplantation (BMT) reverses this effect. Thus, mouse studies have begun to implicate a role for the adaptive immune response in modulating the progression of AD. Yet it remains critical to further define the mechanisms by which lymphocytes influence this disease, and whether similar mechanisms are at work in aging humans. For this proposal we have assembled a multidisciplinary team who bring expertise in AD pathogenesis, transgenic modeling, RNA-sequencing, AD neuroimmunology, T-cell biology, and bone marrow transplantation. Together we will examine the role of adaptive immunity in AD pathogenesis and test the hypothesis that: lymphocytes reduce pathology by modulating microglial activation and phagocytosis and that genetic modifiers of peripheral immunity contribute to the development of AD. To achieve these goals we will take advantage of several unique resources including an immune-deficient transgenic AD model and a collection of over 1000 samples of peripheral blood mononuclear cells (PBMCs) derived from well-characterized AD, mild cognitive impairment (MCI), and control patients. In Aim 1, we will determine which peripheral immune cells infiltrate the brain in AD subjects and transgenic models and whether these cells interact directly or indirectly with microglia to modulate A? clearance. In Aim 2, we will determine which specific peripheral immune cell populations most strongly influence beta-amyloid deposition by adoptively transferring specific immune populations and performing bone marrow transplantation studies to determine which cell types are necessary and sufficient to reduce A?. In Aim 3, we will determine whether AD or MCI subjects exhibit changes in peripheral immune cell populations, cytokine production, or antigen receptor repertoires and whether these changes are influenced by AD GWAS risk polymorphisms? Collectively, these studies will greatly enhance our understanding of the immune response in both AD patients and mouse models and determine whether T and B cells play an important role in this disease by promoting the clearance of beta-amyloid.